1. Field of the Invention
The invention relates generally to methods of treatment for autoimmune diseases. Specifically, the invention relates to methods of treatment for autoimmune diseases using succinylacetone.
2. Description of Related Art
Autoimmune disease is an inflammation triggered by an organism's reactivity to its own tissue. The search for pharmaceutical compositions and methods for treating this disease has been aided by the use of animals in which an experimental model of the disease has been developed. One such disease developed in laboratory animals is known as "experimental autoimmune uveitis" or "EAU." Successful methods for treating this autoimmune disease are useful for treating other autoimmune diseases.
Experimental autoimmune uveitis (EAU) is a T cell dependent model of ocular inflammation which can be induced in Lewis rats by footpad immunization of bovine retinal S-antigen in complete Freund's adjuvant. Retinal S-antigen is a 48K protein derived from the photoreceptors of the retina. Retinal S-antigen functions in phototransduction. The disease model can be transferred by a specific T-cell line but is not transferred by serum. When induced by active immunization, clinical inflammation begins 10 to 12 days after footpad injection. Low levels of antibody can be detected by day 7 after immunization and the popliteal lymphocyte proliferative response peaks at day 10. The inflammation occurs in the photoreceptors of the retina and in the pineal gland, both of which contain S-antigen. The ocular inflammation is characterized by photoreceptor cell loss followed by a more diffuse retinal destruction. The inflammation resolves in 7 to 10 days leaving an atrophic retina with glial remnants and does not spontaneously recur.
This experimental disease is a useful model to study the development and modulation of human ocular inflammation, because both disease conditions respond in approximately the same manner to pharmaceutical compositions and methods of treatment. For example, cyclosporine A has been helpful in regulating both ocular inflammation in experimental animals as well as human uveitis of probable autoimmune origin. Experimental autoimmune uveitis can be inhibited by cyclosporine if the drug is administered on or before day 7 after immunization. However, cyclosporine nephrotoxicity limits the use of this agent in uveitis and other autoimmune disease. Cyclosporine at a dose of 10 mg/kg daily will suppress experimental autoimmune uveitis at day 14 when started on day 0 or day 7 and there is a late relapse of inflammation if the drug is stopped. The development of other strategies for immune modulation of human autoimmune disease is desirable.
Succinylacetone (4,6-dioxoheptanoic acid) is an irreversibIe inhibitor of the second enzyme of the heme biosynthetic pathway, delta-amino levulinic acid dehydrase (ALAD). Although initial studies with this compound focused on its ability to inhibit the growth of erythroleukemic cells, through inhibition of heme biosynthesis, it is also capable of impairing the growth of other tumors by a mechanism independent of heme biosynthesis. This activity is disclosed in the article, Tschudy et al., "Growth Inhibitory Activity of Succinylacetones: Studies with Walker 256 Carcinosarcoma" Oncology 40:148 (1983), hereby incorporated by reference. In spite of the ability of succinylacetone to initially inhibit growth of the Walker 256 tumor, continuous treatment with succinylacetone actually enhanced allogeneic tumor growth in rats. This compound is also active in suppressing rat antibody responses to sheep red blood cells in vivo and in inhibiting mitogen and antigen responses by human lymphocytes in vitro. This characteristic of the compound is disclosed in Tschudy et al., "Immunosuppressive Activity of Succinylacetone" J. Lab & Clin. Medicine 99(4):526 (1982), hereby incorporated by reference.
Succinylacetone was initially believed to have anti-tumor activity via its irreversible inhibition of delta-ALA dehydrase and thus heme biosynthesis. However, further studies showed it was capable of inhibiting the growth of tumors that did not exhibit high levels of heme synthesis and, that prolonged administration resulted in enhanced tumor allograft growth, via an immunosuppressive effect. In spite of the potent effects of succinylacetone, one month of treatment does not demonstrate significant histopathologic abnormalities in any non-lymphoid organ. There is 12% decrease in hematocrit and a 20% decrease in hemoglobin due to suppression of heme production. This decrease in hemoglobin is only 40% of what would be expected if there was total inhibition of heme production.
Succinylacetone has been successfully used to totally inhibit graft vs host disease (GVHD) in allogeneic bone marrow transplantation. In spite of its strong effects on heme synthesis and immune function, succinylacetone does not interfere with engraftment or hematopoietic reconstitution. After one month treatment, there is only a minor depression of hemoglobin and lymphocytes in the blood and these parameters normalized when the drug was stopped. The animals treated by succinylacetone gain weight and no toxicity to other organ systems is seen.
U.S. Pat. No. 4,670,467 to Hess et al., hereby incorporated by reference, discloses a method of controlling graft versus host reaction. This method uses succinylacetone to treat or control this disease which results from bone marrow transplantation. This disclosure, as well as the two disclosures discussed above, do not suggest any method of treatment for autoimmune disease.
The industry is lacking a method for suppressing autoimmune disease. Such a method would also be desirable in modulating the effects of experimental autoimmune uveitis.